The discovery of insulin has saved the lives of millions of people with diabetes around the world, but little is known about the first step in insulin synthesis.
Researchers at the University of Michigan have discovered part of this mystery. Examining the messenger RNAs involved in insulin production in fruit flies, they found that the chemical tag on the mRNA is essential for translating the insulin mRNA into the insulin protein. A change in this chemical tag can affect how much insulin is produced.
The study, conducted by researchers Daniel Wilinski and Monica Dus, was published in the journal Nature Structural and Molecular Biology.
An organism carries DNA—its genes—in every cell of its body. Genes are blocks of information that are transcribed into proteins by other molecules called messenger RNAs. These mRNAs are photocopies of DNA—leaving the original DNA intact—that carry this protein information into the cytoplasm of cells, where protein is synthesized. mRNAs are decorated with small molecules called “tags.” These tags can change how RNA works and how proteins are made.
“I like to think of RNA as a Christmas tree,” said Wilinski, a postdoctoral researcher in Dus’ lab in the UM Department of Molecular, Cellular and Developmental Biology. “Christmas trees are beautiful in the wilderness, but when you bring them inside and put decorations on them, that decoration is how you feel the tree is part of the season. Same thing with RNA. These RNA decorations really enhance the way RNA is regulated.”
Studying insulin production in humans or mammals is difficult. In humans, the pancreas is located behind the liver. It doesn’t reproduce well, and it doesn’t sample live subjects. But in flies, their insulin cells are in their brains, act like neurons, and are physically accessible to researchers. In fruit flies, the researchers looked at a tag called RNA N-6 adenosine methylation, or m6A.
To study the m6A tag, the researchers first identified RNAs with the tag. They then labeled the insulin cells with a fluorescent molecule, and used confocal microscopy to visualize how much insulin the insulin cell was making. They did this under two conditions: first, they removed the m6A enzyme, which is responsible for decorating mRNA with m6A tags, in insulin cells. Second, they removed the m6A tags by using CRISPR, a technology used in DNA editing, to mutate the modified As.
In both cases, the flies’ ability to produce insulin was greatly reduced.
“We found that this DNA photocopy for insulin, this mRNA, has a specific tag that, when it’s there, a ton of insulin hormone is produced,” said Dus, associate professor of molecular, cellular and developmental biology. “But without the signal, the flies have much less insulin and have signs of diabetes.”
This chemical tag is conserved—or unchanged—in fish, mice and humans.
“So it’s likely that insulin production is also regulated by this type of mechanism in humans,” Wilinski said. “There is an epidemic of obesity and diabetes not only in the United States, but around the world. Our finding is one more piece of evidence of how this disease occurs.”
Dus says that the discovery improves the understanding of the biology of insulin and the physiology of energy homeostasis disorders. Low levels of chemical tags are observed in people with type 2 diabetes. Restoring the levels of these tags may also help fight diabetes and metabolic disease, he said.
“We have known about insulin as a treatment for a hundred years. We have discovered a lot about how insulin is made,” said Dus. “But we know very little about the very basic molecular biology of insulin and how it’s regulated. That’s why I think this work is so important—it refocuses on insulin, the gene and all the things we still need to know about it.”
More information:
N6-Adenosine methylation regulates insulin mRNA translation, Nature Structural and Molecular Biology (2023).
Provided by the University of Michigan
Citation: Revealing the biology of insulin production (2023, July 24) retrieved 24 July 2023 from https://phys.org/news/2023-07-revealing-biology-insulin-production.html
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